We propose to apply our expertise in the measurement, analysis and interpretation of autonomic function to develop an index of autonomic neuropathy and then to use this index to assess the progressive effects of the diabetic state upon sympathetic and parasympathetic regulation of cardiovascular function. The ultimate goal of Specific Aim 1 is to develop a non-invasive index for the early detection and management of diabetic autonomic nervous dysfunction. BP and SNA will be recorded in the unanesthetized, diabetes-prone rat (BBDP), and in age-matched diabetes resistant animals (BBDR), at progressive stages before and during the establishment of diabetic dysautonomia. The dynamic relationship between SNA and arterial BP will be analyzed at each stage, and at each of 5 different controlled combinations of plasma glucose and insulin levels. Modern signal processing algorithms will be used to detect and characterize the effects of diabetes upon the coupling of sympathetic and vascular function. The SNA and BP recordings, and the heart rate (HR) power spectrum will be tested along with classical indices of diabetic neuropathy to substantiate the proposed use of very specific aspects of BP and HR recordings to index the development of autonomic dysfunction. The goal of Specific Aim 2 is to quantify the progressive effects of the development of diabetic neuropathy upon (a) the central nervous control of autonomic function and (b) the sympathetic control of peripheral vascular function. The ameliorative effects of exposure to vitamin E upon central and peripheral autonomic control of cardiovascular function will also be tested. These goals will be possible because: (1) we will implant a telemetry device in the subjects prior to their conversion to a diabetic state and monitor their BP, HR and the indices developed in Aim 1 at regular intervals for up to eight months post-conversion; (2) we will train the rats in an acute stress paradigm and evoke this behavioral response at regular intervals before and after their conversion to a diabetic state. Specific components of the stress response result (a) from a """"""""central command"""""""" and (b) from increases in peripheral vascular resistance in response to an increase in SNA. We believe these experiments will help develop better clinical approaches to the control and management of diabetic autonomic neuropathy.
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